A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model.

Anorexia nervosa (AN) is a psychiatric illness with the highest mortality. Current treatment options have been limited to psychotherapy and nutritional support, with low efficacy and high relapse rates. Hypothalamic AgRP (agouti-related peptide) neurons that coexpress AGRP and neuropeptide Y (NPY) play a critical role in driving feeding while also modulating other complex behaviors. We have previously reported that genetic ablation of Tet3, which encodes a member of the TET family dioxygenases, specifically in AgRP neurons in mice, activates these neurons and increases the expression of AGRP, NPY, and the vesicular GABA transporter (VGAT), leading to hyperphagia and anxiolytic effects. Bobcat339 is a synthetic small molecule predicted to bind to the catalytic pockets of TET proteins. Here, we report that Bobcat339 is effective in mitigating AN and anxiety/depressive-like behaviors using a well-established mouse model of activity-based anorexia (ABA). We show that treating mice with Bobcat339 decreases TET3 expression in AgRP neurons and activates these neurons leading to increased feeding, decreased compulsive running, and diminished lethality in the ABA model. Mechanistically, Bobcat339 induces TET3 protein degradation while simultaneously stimulating the expression of AGRP, NPY, and VGAT in a TET3-dependent manner both in mouse and human neuronal cells, demonstrating a conserved, previously unsuspected mode of action of Bobcat339. Our findings suggest that Bobcat339 may potentially be a therapeutic for anorexia nervosa and stress-related disorders.

The impact of anorexia nervosa and BMI polygenic risk on childhood growth: A 20-year longitudinal population-based study.

Growth deviating from the norm during childhood has been associated with anorexia nervosa (AN) and obesity later in life. In this study, we examined whether polygenic scores (PGSs) for AN and BMI are associated with growth trajectories spanning the first two decades of life. AN PGSs and BMI PGSs were calculated for participants of the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 8,654). Using generalized (mixed) linear models, we associated PGSs with trajectories of weight, height, body mass index (BMI), fat mass index (FMI), lean mass index (LMI), and bone mineral density (BMD). Female participants with AN PGSs one standard deviation (SD) higher had, on average, 0.004% slower growth in BMI between the ages 6.5 and 24 years and a 0.4% slower gain in BMD between the ages 10 and 24 years. Higher BMI PGSs were associated with faster growth for BMI, FMI, LMI, BMD, and weight trajectories in both sexes throughout childhood. Female participants with both a high AN PGS and a low BMI PGS showed slower growth compared to those with both a low AN PGS and a low BMI PGS. We conclude that AN PGSs and BMI PGSs have detectable sex-specific effects on growth trajectories. Female participants with a high AN PGS and low BMI PGS likely constitute a high-risk group for AN, as their growth was slower compared to their peers with high PGSs on both traits. Further research is needed to better understand how the AN PGS and the BMI PGS co-influence growth during childhood and whether a high BMI PGS can mitigate the effects of a high AN PGS.

Psilocybin restrains activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms.

Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1 A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors (Htr2a and Htr1a, respectively), and a further reduction in the abundance of Htr2a transcripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.

Systematic reduction of gray matter volume in anorexia nervosa, but relative enlargement with clinical symptoms in the prefrontal and posterior insular cortices: a multicenter neuroimaging study.

Although brain morphological abnormalities have been reported in anorexia nervosa (AN), the reliability and reproducibility of previous studies were limited due to insufficient sample sizes, which prevented exploratory analysis of the whole brain as opposed to regions of interest (ROIs). Objective was to identify brain morphological abnormalities in AN and the association with severity of AN by brain structural magnetic resonance imaging (MRI) in a multicenter study, and to conduct exploratory analysis of the whole brain. Here, we conducted a cross-sectional multicenter study using T1-weighted imaging (T1WI) data collected between May 2014 and February 2019 in Japan. We analyzed MRI data from 103 female AN patients (58 anorexia nervosa restricting type [ANR] and 45 anorexia nervosa binge-purging type [ANBP]) and 102 age-matched female healthy controls (HC). MRI data from five centers were preprocessed using the latest harmonization method to correct for intercenter differences. Gray matter volume (GMV) was calculated from T1WI data of all participants. Of the 205 participants, we obtained severity of eating disorder symptom scores from 179 participants, including 87 in the AN group (51 ANR, 36 ANBP) and 92 HC using the Eating Disorder Examination Questionnaire (EDE-Q) 6.0. GMV reduction were observed in the AN brain, including the bilateral cerebellum, middle and posterior cingulate gyrus, supplementary motor cortex, precentral gyrus medial segment, and thalamus. In addition, the orbitofrontal cortex (OFC), ventromedial prefrontal cortex (vmPFC), rostral anterior cingulate cortex (ACC), and posterior insula volumes showed positive correlations with severity of symptoms. This multicenter study was conducted with a large sample size to identify brain morphological abnormalities in AN. The findings provide a better understanding of the pathogenesis of AN and have potential for the development of brain imaging biomarkers of AN. Trial Registration: UMIN000017456. https://center6.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000019303 .

Influence of the gut microbiome on appetite-regulating neuropeptides in the hypothalamus: Insight from conventional, antibiotic-treated, and germ-free mouse models of anorexia nervosa.

Recent research highlights the profound impact of the gut microbiome on neuropsychiatric disorders, shedding light on its potential role in shaping human behavior. In this study, we investigate the role of the gut microbiome in appetite regulation using activity-based anorexia (ABA) mouse model of anorexia nervosa (AN) - a severe eating disorder with significant health consequences. ABA was induced in conventional, antibiotic-treated, and germ-free mice. Our results show the clear influence of the gut microbiome on the expression of four orexigenic (neuropeptide Y, agouti-related peptide, melanin-concentrating hormone, and orexin) and four anorexigenic peptides (cocaine- and amphetamine-regulated transcript, corticotropin-releasing hormone, thyrotropin-releasing hormone, and pro-opiomelanocortin) in the hypothalamus. Additionally, we assessed alterations in gut barrier permeability. While variations were noted in germ-free mice based on feeding and activity, they were not directly attributable to the gut microbiome. This research emphasizes that the gut microbiome is a pivotal factor in AN's appetite regulation beyond just dietary habits or physical activity.

New perspectives on the role of biological factors in anorexia nervosa: Brain volume reduction or oxidative stress, which came first?

Anorexia nervosa (AN) is an eating disorder (ED) that has seen an increase in its incidence in the last thirty years. Compared to other psychosomatic disorders, ED can be responsible for many major medical complications, moreover, in addition to the various systemic impairments, patients with AN undergo morphological and physiological changes affecting the cerebral cortex. Through immunohistochemical studies on portions of postmortem human brain of people affected by AN and healthy individuals, and western blot studies on leucocytes of young patients and healthy controls, this study investigated the role in the afore-mentioned processes of altered redox state. The results showed that the brain volume reduction in AN could be due to an increase in the rate of cell death, mainly by apoptosis, in which mitochondria, main cellular organelles affected by a decreased dietary intake, and a highly compromised intracellular redox balance, may play a pivotal role.

Positive thinking about negative studies.

The non-reporting of negative studies results in a scientific record that is incomplete, one-sided and misleading. The consequences of this range from inappropriate initiation of further studies that might put participants at unnecessary risk to treatment guidelines that may be in error, thus compromising day-to-day clinical practice.

From awareness to action: an urgent call to reduce mortality and improve outcomes in eating disorders.

High mortality rates and poor outcomes from eating disorders, especially anorexia nervosa, are largely preventable and require urgent action. A national strategy to address this should include prevention; early detection; timely access to integrated physical and psychological treatments; safe management of emergencies; suicide prevention; and investment in training, services and research.

Not niche: eating disorders as an example in the dangers of overspecialisation.

Labelling specific psychiatric concerns as 'niche' topics relegated to specialty journals obstructs high-quality research and clinical care for these issues. Despite their severity, eating disorders are under-represented in high-impact journals, underfunded, and under-addressed in psychiatric training. We provide recommendations to stimulate broad knowledge dissemination for under-acknowledged, yet severe, psychiatric disorders.

Change in food choice during acute treatment and the effect on longer-term outcome in patients with anorexia nervosa.

BACKGROUND: Restriction of food intake is a central pathological feature of anorexia nervosa (AN). Maladaptive eating behavior and, specifically, limited intake of calorie-dense foods are resistant to change and contribute to poor long-term outcomes. This study is a preliminary examination of whether change in food choices during inpatient treatment is related to longer-term clinical course. METHODS: Individuals with AN completed a computerized Food Choice Task at the beginning and end of inpatient treatment to determine changes in high-fat and self-controlled food choices. Linear regression and longitudinal analyses tested whether change in task behavior predicted short-term outcome (body mass index [BMI] at discharge) and longer-term outcome (BMI and eating disorder psychopathology). RESULTS: Among 88 patients with AN, BMI improved significantly with hospital treatment (p < 0.001), but Food Choice Task outcomes did not change significantly. Change in high-fat and self-controlled choices was not associated with BMI at discharge (r = 0.13, p = 0.22 and r = 0.10, p = 0.39, respectively). An increase in the proportion of high-fat foods selected (ß = 0.91, p = 0.02) and a decrease in the use of self-control (ß = -1.50, p = 0.001) predicted less decline in BMI over 3 years after discharge. CONCLUSIONS: Short-term treatment is associated with improvement in BMI but with no significant change, on average, in choices made in a task known to predict actual eating. However, the degree to which individuals increased high-fat choices during treatment and decreased the use of self-control over food choice were associated with reduced weight loss over the following 3 years, underscoring the need to focus on changing eating behavior in treatment of AN.

Interplay of polygenic liability with birth-related, somatic, and psychosocial factors in anorexia nervosa risk: a nationwide study.

BACKGROUND: Although several types of risk factors for anorexia nervosa (AN) have been identified, including birth-related factors, somatic, and psychosocial risk factors, their interplay with genetic susceptibility remains unclear. Genetic and epidemiological interplay in AN risk were examined using data from Danish nationwide registers. AN polygenic risk score (PRS) and risk factor associations, confounding from AN PRS and/or parental psychiatric history on the association between the risk factors and AN risk, and interactions between AN PRS and each level of target risk factor on AN risk were estimated. METHODS: Participants were individuals born in Denmark between 1981 and 2008 including nationwide-representative data from the iPSYCH2015, and Danish AN cases from the Anorexia Nervosa Genetics Initiative and Eating Disorder Genetics Initiative cohorts. A total of 7003 individuals with AN and 45 229 individuals without a registered AN diagnosis were included. We included 22 AN risk factors from Danish registers. RESULTS: Risk factors showing association with PRS for AN included urbanicity, parental ages, genitourinary tract infection, and parental socioeconomic factors. Risk factors showed the expected association to AN risk, and this association was only slightly attenuated when adjusted for parental history of psychiatric disorders or/and for the AN PRS. The interaction analyses revealed a differential effect of AN PRS according to the level of the following risk factors: sex, maternal age, genitourinary tract infection, C-section, parental socioeconomic factors and psychiatric history. CONCLUSIONS: Our findings provide evidence for interactions between AN PRS and certain risk-factors, illustrating potential diverse risk pathways to AN diagnosis.

Shared genetic influences between eating disorders and gastrointestinal disease in a large, population-based sample of adult women and men.

BACKGROUND: Some preliminary research suggests higher rates of gastrointestinal disease in individuals with eating disorders (EDs). However, research is limited, and it remains unknown what etiologic factors account for observed associations. This was the first study to examine how EDs and dimensional ED symptoms (e.g. body dissatisfaction, binge eating) are phenotypically and etiologically associated with gastrointestinal disease in a large, population-based twin sample. METHODS: Adult female (N = 2980) and male (N = 2903) twins from the Michigan State University Twin Registry reported whether they had a lifetime ED (anorexia nervosa, bulimia nervosa, or binge-eating disorder) and completed a measure of dimensional ED symptoms. We coded the presence/absence of lifetime gastrointestinal disease (e.g. inflammatory bowel disease) based on responses to questions regarding chronic illnesses and medications. We first examined whether twins with gastrointestinal disease had higher rates of EDs and ED symptoms, then used correlated factors twin models to investigate genetic and environmental contributions to the overlap between disorders. RESULTS: Twins with gastrointestinal disease had significantly greater dimensional ED symptoms (ß = 0.21, p < 0.001) and odds of a lifetime ED (OR 2.90, p = 0.001), regardless of sex. Shared genetic factors fully accounted for the overlap between disorders, with no significant sex differences in etiologic associations. CONCLUSIONS: Comorbidity between EDs and gastrointestinal disease may be explained by overlap in genetic influences, potentially including inflammatory genes implicated in both types of disorders. Screening for gastrointestinal disease in people with EDs, and EDs in those with gastrointestinal disease, is warranted.

Longitudinal changes in brain-derived neurotrophic factor (BDNF) but not cytokines contribute to hippocampal recovery in anorexia nervosa above increases in body mass index.

BACKGROUND: Physical sequelae of anorexia nervosa (AN) include a marked reduction in whole brain volume and subcortical structures such as the hippocampus. Previous research has indicated aberrant levels of inflammatory markers and growth factors in AN, which in other populations have been shown to influence hippocampal integrity. METHODS: Here we investigated the influence of concentrations of two pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]) and brain-derived neurotrophic factor (BDNF) on the whole hippocampal volume, as well as the volumes of three regions (the hippocampal body, head, and tail) and 18 subfields bilaterally. Investigations occurred both cross-sectionally between acutely underweight adolescent/young adult females with AN (acAN; n = 82) and people recovered from AN (recAN; n = 20), each independently pairwise age-matched with healthy controls (HC), and longitudinally in acAN after partial renourishment (n = 58). Hippocampal subfield volumes were quantified using FreeSurfer. Concentrations of molecular factors were analyzed in linear models with hippocampal (subfield) volumes as the dependent variable. RESULTS: Cross-sectionally, there was no evidence for an association between IL-6, TNF-α, or BDNF and between-group differences in hippocampal subfield volumes. Longitudinally, increasing concentrations of BDNF were positively associated with longitudinal increases in bilateral global hippocampal volumes after controlling for age, age2, estimated total intracranial volume, and increases in body mass index (BMI). CONCLUSIONS: These findings suggest that increases in BDNF may contribute to global hippocampal recovery over and above increases in BMI during renourishment. Investigations into treatments targeted toward increasing BDNF in AN may be warranted.

Comprehensive elucidation of resting-state functional connectivity in anorexia nervosa by a multicenter cross-sectional study.

BACKGROUND: Previous research on the changes in resting-state functional connectivity (rsFC) in anorexia nervosa (AN) has been limited by an insufficient sample size, which reduced the reliability of the results and made it difficult to set the whole brain as regions of interest (ROIs). METHODS: We analyzed functional magnetic resonance imaging data from 114 female AN patients and 135 healthy controls (HC) and obtained self-reported psychological scales, including eating disorder examination questionnaire 6.0. One hundred sixty-four cortical, subcortical, cerebellar, and network parcellation regions were considered as ROIs. We calculated the ROI-to-ROI rsFCs and performed group comparisons. RESULTS: Compared to HC, AN patients showed 12 stronger rsFCs mainly in regions containing dorsolateral prefrontal cortex (DLPFC), and 33 weaker rsFCs primarily in regions containing cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between anterior cingulate cortex (ACC) and thalamus (p < 0.01, false discovery rate [FDR] correction). Comparisons between AN subtypes showed that there were stronger rsFCs between right lingual gyrus and right supracalcarine cortex and between left temporal occipital fusiform cortex and medial part of visual network in the restricting type compared to the binge/purging type (p < 0.01, FDR correction). CONCLUSION: Stronger rsFCs in regions containing mainly DLPFC, and weaker rsFCs in regions containing primarily cerebellum, within temporal lobe, between posterior fusiform cortex and lateral part of visual network, and between ACC and thalamus, may represent categorical diagnostic markers discriminating AN patients from HC.

Reduced dorsal fronto-striatal connectivity at rest in anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a serious psychiatric illness that remains difficult to treat. Elucidating the neural mechanisms of AN is necessary to identify novel treatment targets and improve outcomes. A growing body of literature points to a role for dorsal fronto-striatal circuitry in the pathophysiology of AN, with increasing evidence of abnormal task-based fMRI activation within this network among patients with AN. Whether these abnormalities are present at rest and reflect fundamental differences in brain organization is unclear. METHODS: The current study combined resting-state fMRI data from patients with AN (n = 89) and healthy controls (HC; n = 92) across four studies, removing site effects using ComBat harmonization. First, the a priori hypothesis that dorsal fronto-striatal connectivity strength - specifically between the anterior caudate and dlPFC - differed between patients and HC was tested using seed-based functional connectivity analysis with small-volume correction. To assess specificity of effects, exploratory analyses examined anterior caudate whole-brain connectivity, amplitude of low-frequency fluctuations (ALFF), and node centrality. RESULTS: Compared to HC, patients showed significantly reduced right, but not left, anterior caudate-dlPFC connectivity (p = 0.002) in small-volume corrected analyses. Whole-brain analyses also identified reduced connectivity between the right anterior caudate and left superior frontal and middle frontal gyri (p = 0.028) and increased connectivity between the right anterior caudate and right occipital cortex (p = 0.038). No group differences were found in analyses of anterior caudate ALFF and node centrality. CONCLUSIONS: Decreased coupling of dorsal fronto-striatal regions indicates that circuit-based abnormalities persist at rest and suggests this network may be a potential treatment target.

Brain-based gene expression of putative risk genes for anorexia nervosa.

The etiology of anorexia nervosa (AN) remains elusive. Recent genome-wide association studies identified the first genes liked to AN which reached genome-wide significance, although our understanding of how these genes confer risk remains preliminary. Here, we leverage the Allen Human Brain Atlas to characterize the spatially distributed gene expression patterns of genes linked to AN in the non-disordered human brain, developing whole-brain maps of AN gene expression. We found that genes associated with AN are most expressed in the brain, relative to all other body tissue types, and demonstrate gene-specific expression patterns which extend to cerebellar, temporal and basal ganglia structures in particular. fMRI meta-analyses reveal that AN gene expression maps correspond with functional brain activity involved in processing and anticipating appetitive and aversive cues. Findings offer novel insights around putative mechanisms through which genes associated with AN may confer risk.

Exploring the influence of circulating endocannabinoids and nucleus accumbens functional connectivity on anorexia nervosa severity.

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by a harmful persistence of self-imposed starvation resulting in significant weight loss. Research suggests that alterations in the nucleus accumbens (NAcc) and circulating endocannabinoids (eCBs), such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), may contribute to increased severity and maladaptive behaviors in AN, warranting an examination of the interplay between central reward circuitry and eCBs. For this purpose, we assessed NAcc functional connectivity and circulating AEA and 2-AG concentrations in 18 individuals with AN and 18 healthy controls (HC) to test associations between circulating eCBs, NAcc functional connectivity, and AN severity, as defined by body mass index (BMI). Decreased connectivity was observed between the NAcc and the right insula (NAcc-insula; pFWE < 0.001) and the left supplementary motor area (NAcc-SMA; pFWE < 0.001) in the AN group compared to HC. Reduced NAcc-insula functional connectivity mediated the association between AEA concentrations and BMI in the AN group. However, in HC, NAcc-SMA functional connectivity had a mediating role between AEA concentrations and BMI. Although no significant differences in eCBs concentrations were observed between the groups, our findings provide insights into how the interaction between eCBs and NAcc functional connectivity influences AN severity. Altered NAcc-insula and NAcc-SMA connectivity in AN may impair the integration of interoceptive, somatosensory, and motor planning information related to reward stimuli. Furthermore, the distinct associations between eCBs concentrations and NAcc functional connectivity in AN and HC could have clinical implications for weight maintenance, with eCBs being a potential target for AN treatment.

AgRP neurons coordinate the mitigation of activity-based anorexia.

Anorexia nervosa (AN) is a debilitating and deadly disease characterized by low body mass index due to diminished food intake, and oftentimes concurrent hyperactivity. A high percentage of AN behavioral and metabolic phenotypes can be replicated in rodents given access to a voluntary running wheel and subject to food restriction, termed activity-based anorexia (ABA). Despite the well-documented bodyweight loss observed in AN human patients and ABA rodents, much less is understood regarding the neurobiological underpinnings of these maladaptive behaviors. Hunger-promoting hypothalamic agouti-related peptide (AgRP) neurons have been well characterized in their ability to regulate appetite, yet much less is known regarding their activity and function in the mediation of food intake during ABA. Here, feeding microstructure analysis revealed ABA mice decreased food intake due to increased interpellet interval retrieval and diminished meal number. Longitudinal activity recordings of AgRP neurons in ABA animals exhibited a maladaptive inhibitory response to food, independent of basal activity changes. We then demonstrated that ABA development or progression can be mitigated by chemogenetic AgRP activation through the reprioritization of food intake (increased meal number) over hyperactivity, but only during periods of food availability. These results elucidate a potential neural target for the amelioration of behavioral maladaptations present in AN patients.

Long-Term Dynamics of Serum α-MSH and α-MSH-Binding Immunoglobulins with a Link to Gut Microbiota Composition in Patients with Anorexia Nervosa.

INTRODUCTION: Immunoglobulins (Ig) reactive with α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide, are present in humans and were previously associated with eating disorders. In this longitudinal study involving patients with anorexia nervosa (AN), we determined whether α-MSH in serum is bound to IgG and analyzed long-term dynamics of both α-MSH peptide and α-MSH-reactive Ig in relation to changes in BMI and gut microbiota composition. METHODS: The study included 64 adolescents with a restrictive form of AN, whose serum samples were collected at hospital admission, discharge, and during a 1-year follow-up visit and 41 healthy controls, all females. RESULTS: We found that in both study groups, approximately 40% of serum α-MSH was reversibly bound to IgG and that levels of α-MSH-reactive IgG but not of α-MSH peptide in patients with AN were low at hospital admission but recovered 1 year later. Total IgG levels were also low at admission. Moreover, BMI-standard deviation score correlated positively with α-MSH IgG in both groups studied but negatively with α-MSH peptide only in controls. Significant correlations between the abundance of specific bacterial taxa in the gut microbiota and α-MSH peptide and IgG levels were found in both study groups, but they were more frequent in controls. CONCLUSION: We conclude that IgG in the blood plays a role as an α-MSH-binding protein, whose characteristics are associated with BMI in both patients with AN and controls. Furthermore, the study suggests that low production of α-MSH-reactive IgG during the starvation phase in patients with AN may be related to altered gut microbiota composition.

Altered learning from positive feedback in adolescents with anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) is characterized by severe restriction of calorie intake, which persists despite serious medical and psychological sequelae of starvation. Several prior studies have identified impaired feedback learning among individuals with AN, but whether it reflects a disturbance in learning from positive feedback (i.e., reward), negative feedback (i.e., punishment), or both, and the extent to which this impairment is related to severity and duration of illness, has not been clarified. METHOD: Participants were female adolescents with AN (n = 76) and healthy teen volunteers (HC; n = 38) between the ages of 12-18 years who completed a probabilistic reinforcement learning task. A Bayesian reinforcement learning model was used to calculate separate learning rates for positive and negative feedback. Exploratory analyses examined associations between feedback learning and duration of illness, eating disorder severity, and self/parent reports of reward and punishment sensitivity. RESULTS: Adolescents with AN had a significantly lower rate of learning from positive feedback relative to HC. Patients and HC did not differ in learning from negative feedback or on overall task performance measures. Feedback learning parameters were not significantly associated with duration of illness, eating disorder severity, or questionnaire-based reports of reward and punishment sensitivity. CONCLUSION: Adolescents with AN showed a circumscribed deficit in learning from reward that was not associated with duration of illness or reported sensitivity to reward or punishment. Subsequent longitudinal research should explore whether differences in learning from positive feedback relate to course of illness in youth with AN.